合成路线1

3-Chloro-4-(2-pyridylmethoxy)aniline (I) is condensed with ethyl cyanoacetate (II) at 100-115 °C to give the N-aryl 2-cyanoacetamide (III). Reduction of 3-ethoxy-4-phthalimido-1-nitrobenzene (IV) with H2 over Pd/C in THF at 50 °C followed by coupling of the resulting aniline with the cyano amide (III) by means of triethyl orthoformate in refluxing propanol affords the 3-amino-2-cyanopropenamide derivative (V). After intramolecular cyclization of propenamide (V) by means of POCl3 in acetonitrile at 60-70 °C, the obtained 6-phthalimidoquinoline derivative is hydrolyzed by means of NH4OH in EtOH at 62-68 °C to give the 6-aminoquinoline (VI) (1). Alternatively, the aminoquinoline (VI) can be obtained by condensation of the aniline derivative (I) with 6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile (VII) in the presence of methanesulfonic acid at 70-75 °C, affording the diarylamine (VIII), which is then deacetylated to the aminoquinoline (VI) by hydrolysis with HCl . Finally, compound (VI) is acylated with 4-(dimethylamino)-2-butenoyl chloride (IX) , obtained by chlorination of the corresponding free acid (X) or its hydrochloride salt with either (COCl)2 by means of DMF in THF or DMF/i-PrOAc , POCl3 in DMAc, or SOCl2 in DMAc , in the presence of NMP .
In a related strategy, 4-chloro-7-ethoxy-6-nitroquinoline-3-carbonitrile (XI) is reduced to the corresponding amine (XII) by means of Fe and acetic acid in refluxing methanol. Subsequent acylation of (XII) with 4-(dimethylamino)-2-butenoyl chloride (IX) in the presence of NMP in acetonitrile or DMF yields carboxamide (XIII), which is finally coupled with 3-chloro-4-(2-pyridylmethoxy)aniline (I) by means of pyridinium chloride in refluxing isopropanol or 2-methoxyethanol .